Controlled release simvastatin delivery device

ABSTRACT

Controlled delivery of a beneficial agent in a dispersion is provided using (i) a compressed core which contains the beneficial agent, a polymer which forms gelatinous microscopic particles upon hydration, and if desired, an agent to modulate the hydration; and (ii) a water insoluble coating which adheres to and surrounds the core and contains apertures which provide an area for the hydration and release of the dispersion. The release rate of the beneficial agent is a function of the number and size of the apertures in the coating.

RELATED APPLICATIONS

In accordance with 35 USC 371, this application is a continuation ofPCT/US95/13693, which was internationally filed Oct. 19, 1995, anditself is a continuation of U.S. Ser. No. 08/327,083, filed Oct. 21,1994, now issued as U.S. Pat. No. 5,543,154, which itself is acontinuation-in-part of U.S. Ser. No. 08/118,836, filed Sep. 8, 1993,now issued as U.S. Pat. No. 5,366,738, which itself is a continuation ofU.S. Ser. No. 07/902,188, filed Jul. 29, 1992, now abandoned, and itselfis a continuation-in-part of U.S. Ser. No. 07/815,304, filed Dec. 27,1991, now abandoned.

FIELD OF THE INVENTION

This invention pertains to both a useful and novel drug-delivery devicefor dispensing a drug to an environment of use. Particularly, theinvention pertains to a system that releases a drug in a controlledfashion, by creating gelatinous microscopic particles of polymer gel andin so doing, generates a dispersion of drug among the microscopicparticles. The dispersion then moves from the device surface into theaqueous environment of use.

The device is composed of a core containing a beneficial agent such as amedicament, a polymer which provides gelatinous microscopic particlesupon hydration and if desired a hydration modulating agent. The deviceis completely coated with an insoluble, impermeable coating. The deviceis completely coated with an insoluble, impermeable coating. The coatingcontains apertures to expose discrete portions of the surface of thecore. The delivery rate of the medicament is a function of the corecomposition as well as the number and size of the apertures.

In the environment of use, biological fluid contacts the exposedportions of the core surface where hydration of the polymer at thesurface begins. As the particles of polymer at the exposed surfaceabsorb water, a gelatinous microscopic dispersion of particles results.Mixed with and dispersed in these microscopic particles are the othercomponents of the core formulation, such as a medicament.

The exposed portion of the core surface is bounded on all sides by thecoating. Hydration of the polymer occurs only at the exposed surface ofthe core, resulting in the steady-state formulation of a gelatinousmicroscopic particle dispersion within which the drug is dispensed andwhich moves into the environment of use.

The rate of release of the beneficial agent is not dependent upon thesolubility of the beneficial agent in the biological fluid. Rather, therelease rate is essentially dependent upon the rate at which thegelatinous microscopic particle dispersion forms at the exposed surfaceof the device core and exudes from the device carrying with it thebeneficial agent and any other core excipient materials that arepresent.

BACKGROUND OF THE INVENTION

The need for systems that can deliver any drug at a controlled rate ofrelease to an environment of use over a specified period of time is wellestablished.

U.S. Pat. No. 4,814,182 discloses the use of rods or slabs ofpre-hydrated and swelled polyethylene oxide hydrogel. The polymer isimpregnated with a biologically active agent during the hydrationprocedure. The hydrated polymer is then dried and partially coated withan impermeable, insoluble material. When placed in an aqueousenvironment, the polymer swells, but does not dissolve or disintegrate.The entrapped active ingredient is released from the polymer bydiffusion. The mechanism of release is based on the ability of thesoluble drug to diffuse through the rehydrated hydrogel and move intothe aqueous environment.

U.S. Pat. No. 4,839,177 discloses the use of hydrogels compressed todefined geometric forms. In this device, the polymer is mixed withbiologically active ingredients to form a core which is affixed to a"support platform" made of an insoluble polymeric material. Whenhydrated, the swellable, gellable hydrogel expands beyond the device andestablishes a superstructure from which the active agent is releasedeither by diffusion, if the active agent is soluble, or by erosion, ifthe active agent is insoluble. The generation and maintenance of thesuperstructure is vital to the proper operation of this device.

An osmotic dosage form which utilizes a semipermeable wall containing atleast one "exit means" which passes through the wall surrounding a corecontaining an osmotic agent, a neutral and ionizable hydrogel and anactive ingredient is taught in U.S. Pat. No. 4,971,790. The coating ofthis device is permeable to water from the environment of use. Watermoves into the core through the semipermeable membrane. Once inside thedevice, the water solubilizes the osmotic agent, and hydrates thehydrogels Pressure builds up inside the device, (due to the ionizationof the osmogent). Ultimately, the solubilized, ionizable hydrogel,containing the beneficial agent, (the neutral hydrogel) and other coreexcipients are pumped out of the core, under pressure through an exitmeans and into the environment of use.

The existing technology is limited since diffusion controlled systemsare effective only when soluble active agents are dispensed. Forosmotically controlled devices, the technoloy relies upon a wallpermeable to the passage of fluid present in the environment of use.Furthermore, these devices require a wall of carefully controlledpermeability.

Devices that rely upon the establishment of an extra devicesuperstructure can be altered during in vivo transit, for example, inthe gastrointestinal tract. If portions of the superstructure breakaway, greater surface area is displayed to the environment andunpredictable release of the active agent results.

The usefulness of the above devices would be increased if a device andmethod were provided to improve the delivery of drugs without regard totheir solubility so that diffusion from a swelled polymer or through thesuperstructure of a polymeric matrix could be avoided. Further utilityresults from a methodology which provides for a device where thegeneration of an extra tablet structure could be avoided and the dryingredients could be contained within a protective coating until releasefrom the device. This would prevent the chance of premature erosion anduncontrolled release of the active agent as well as provide enhancedstability for those active agents that are labile in the fluid of theenvironment of use.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a schematic representation of one embodiment of the instantinvention. The device 10, has a core composition 11, comprised of abeneficial agent 12, gel forming polymer 13, capable of forming agelatinous microscopic particle dispersion upon hydration. The core mayoptionally contain a polymer hydration modulating agent 14 and othertablet forming excipients 15. The core is surrounded by an insoluble,impermeable coating 16, with a plurality of apertures 17 which exposethe core surface to the environment of use.

FIG. 2 is a graph showing the percent of drug released over time fromdevices of the invention, the devices having a drug:core polymer w/wratio of 1:3: and 1:1 and wherein the coating polymers are polyvinylchloride (PVC) or cellulose acetate butyrate (CAB). See Examples 1-4.

FIG. 3 is a graph showing the percent of drug (simvastatin) releasedover time from a device of the invention wherein the w/w ratio ofdrug:core polymer is 1:1 and the polymer coating is cellulose acetatebutyrate. See Example 5.

FIG. 4 is a graph showing the percent of drug (lovastatin) released froma device of the invention wherein the w:w ratio of drug:core polymer is1:1 and the polymer coating is cellulose acetate butyrate. See Example 6

FIG. 5 is a graph showing the percent of drug (simvastatin) releasedfrom a device of the invention wherein the w:w ratio of drug:corepolymer is 40:26.7 and the polymer coating is cellulose acetatebutyrate. See Example 7

FIG. 6 is a graph showing the percent of drug (lovastatin) released froma device of the invention wherein the w:w ratio of drug:core polymer is40:16 and the polymer coating is cellulose acetate butyrate. See Example8

FIG. 7 is a graph showing the percent of drug (acetaminophen) releasedfrom a device of the invention wherein the w:w ratio of drug:corepolymer is 2:1 and the polymer coating is cellulose acetate butyrate.See Example 9.

In operation, aqueous solution, from the environment of use, contactsthe surface of the core that is exposed within the apertures 17. Theavailable water begins to hydrate the (microscopic gel bead forming)polymer 13 and gelatinous microscopic particles form at the surface ofthe core. If present, the polymer hydration modulating agent 14, at theexposed core surface, is solubilized and establishes the environmentrequired for controlled hydration of the polymer.

As the polymer particles 13 are hydrated, the gelatinous microscopicparticles move from the surface. At the same time, the gelatinousmicroscopic particles move the beneficial agent 12 from the surroundingsurface into the environment as well. These particles of beneficialagent move from the core surface into the environment of use in adispersion with the gelatinous microscopic particles. As a result,controlling the surface area of the core, which is exposed to theenvironment of use, effectively controls the delivery rate of medicamentto the environment.

The instant invention provides a novel device for delivery of an activeor beneficial agent (drug), in a dispersion, and produces a beneficialeffect which overcomes the disadvantages associated with prior artdevices.

The instant invention also provides a device for delivering an active orbeneficial agent, in situ as a suspension, at controlled rate over aspecified period of time, which delivery is controlled by the selectionof components of the device and not the environment surrounding thedevice.

Further, the instant invention provides a device for controlled deliveryof an beneficial agent where the release rate of the beneficial agent isneither related to the solubility of the beneficial agent nor to the invivo establishment of an extra tablet superstructure.

Additionally, the instant invention provides a device for controlleddelivery of an beneficial agent where delivery occurs from the surfaceof the device not from within a core so that delivery rate is notdependent on diffusion of the active ingredient from inside the deviceto the environment

Other features and advantages of the invention will be apparent to thoseskilled in the art from the following detailed description of theinvention, taken in conjunction with the drawings and accompanyingclaims.

DETAILED DESCRIPTION OF THE INVENTION

The novel device of this invention consists essentially of a drugdelivery device for the controlled in situ production and release of adispersion containing a beneficial agent, consisting essentially of:

(A) a compressed core prepared from an admixture comprising

(i) a therapeutically effective amount of a beneficial agent and

(ii) a polymer, which upon hydration forms gelatinous microscopicparticles;

(B) a water insoluble, water impermeable polymeric coating, whichsurrounds and adheres to the core, the coating having a plurality ofapertures exposing between about 1 and about 75% of the core surface.

By "drug delivery device" is meant, a dosage form that provides aconvenient means of delivering a drug to a subject. The subject can be ahuman or any other animal. The device is designed to be useful for thedelivery of a drug by any pharmaceutically accepted means such as byswallowing, retaining it within the mouth until the beneficial agent hasbeen dispensed, placing it within the buccal cavity, or the like.

By "controlled" production is meant that the rate of release of thebeneficial agent, that is the amount of beneficial agent released fromthe device to the environment of use, follows a predetermined pattern.Thus, relatively constant or predictably varying amounts of thebeneficial agent can be dispensed over a specified period of time.

The "gelatinous microscopic particles" are composed of discreteparticles of hydrated polymer. Both size and hydration rate of thesegelatinous microscopic particles are characteristics of the individualpolymers. Illustrative of this type of polymer are sodium polyacrylate,particularly those compositions sold under the trade names "AQUAKEEP®J-550", "AQUAKEEP® J-400", which are trade names for sodium acrylatepolymer produced by Seitetsu Kagaku Co., Ltd., Hyogo, Japan. The"AQUAKEEP®" polymers are generically described in U.S. Pat. No.4,340,706. Also illustrative of this type of polymer arecarboxypolymethylenes prepared from acrylic acid crosslinked with allylethers of sucrose or pentaerythritol and sold under the trade names"CARBOPOL® 934P" and "CARBOPOL® 974P" which are trade names for twocarbomer type polymers produced by B. F. Goodrich Chemical Company,Cleveland, Ohio. These latter polymers are generically described in U.S.Pat. No. 2,909,462 and in the National Formulary XVII at p. 1911, CASRegistry Number 9003-01-4. All of the foregoing references are herebyincorporated by reference.

In the dry state, "CARBOPOL 974P" and "CARBOPOL 934P" particles range insize from 2 to about 7 microns. When these articles are hydrated,gelatinous microscopic particles in the range of 20 microns areproduced. When "AQUAKEEP J-550" or "AQUAKEEP J-400" particles arehydrated, the diameter of the gelatinous microscopic particles can rangein size from 100 to 1000 microns.

Once the drug delivery device is within the environment of use, thepolymer of the compressed core which is exposed to the ambient aqueoussolution at the coating apertures, begins to hydrate (the polymer) andproduce gelatinous microscopic particles. By "in situ production andrelease of a dispersion" is meant that during the production of thegelatinous microscopic particles, soluble and insoluble core componentslocated near the polymer particles become dispersed and mixed in such amanner that a gelatinous dispersion is produced. The dispersion movesfrom the device into the aqueous solvent, bringing the beneficial agentinto the environment of use. In this novel device, the components of thecompressed core move into the environment of use, carried along by thegelatinous microscopic particles, continually exposing new surfaces forfurther hydration and production of the dispersion.

By ("gel") or "gelatinous" is meant a semisolid system consisting ofhydrated polymer interpenetrated by the aqueous solvent of theenvironment of use.

By "exude" is meant to discharge gradually or emit gradually from theapperatures of the device.

By "compressed core" is meant that an admixture of ingredientscomprising a beneficial agent, a polymer which produces gelatinousmicroscopic particles when hydrated, and other ingredients that mayaffect any of (1) the rate of production of the dispersion; (2) thestability of the components of the dosage form; or (3) the mixing orcompression characteristics of the admixture, is blended in such a wayto produce a uniform product. This uniform product is then compressedwithin a die to produce a desired form, normally in the shape of atablet, capsule or bolus.

The compressed core contains a therapeutically effective amount ofbeneficial agent and a polymer which upon hydration results inmicroscopic gel beads. The term "beneficial agent" broadly includes anydrug or mixture thereof that can be delivered from the system to producea beneficial result. The drug can be soluble in the fluid that makescontact with the exposed surface of the core, or it can be essentiallyinsoluble in the fluid.

In the specification and the accompanying claims, the term "drug" andits equivalents includes any physiologically or pharmacologically activesubstance that produces a localized or systemic effect or effects inanimals. The term "animal" includes mammals, humans and primates such asdomestic, household, sport or farm animals such as sheep, goats, cattle,horses and pigs, laboratory animals such as mice, rats and guinea pigs,fishes, avians, reptiles and zoo animals.

The active drug that can be delivered by the novel device of thisinvention, includes inorganic and organic compounds without limitation,including drugs that act on the peripheral nerves, adrenergic receptors,cholinergic receptors, nervous system, skeletal muscles, cardiovascularsystem, smooth muscles, blood circulatory system, synaptic sites,neuroeffector junctional sites, endocrine and hormone systems,immunological system, reproductive system, skeletal systems, autocoidsystems, alimentary and excretory systems, inhibitory and histaminesystems, and those materials that act on the central nervous system suchas hypnotics and sedatives.

Examples of beneficial drugs are disclosed in Remington's PharmaceuticalSciences, 16th Ed., 1980, published by Mack Publishing Co., Eaton, Pa.;The Pharmacological Basis of Therapeutics, by Goodman and Gilman, 6thEd., 1980, published by the MacMillan Company, London; and The MerckIndex, 11th Edition, 1989, published by Merck & Co., Rahway, N.J. Thedissolved drug can be in various forms, such as charged molecules,charged molecular complexes or ionizable salts. Acceptable saltsinclude, but are not limited to hydrochlorides, hydrobromide, sulfate,laurylate, palmitate, phosphate, nitrate, borate, acetate, maleate,malate, succinate, tromethamine, tartrate, oleate, salicylate, salts ofmetals, and amines or organic cations, for example quaternary ammonium.

Derivatives of drugs such as esters, ethers and amides without regard totheir ionization and solubility characteristics can be used alone ormixed with other drugs. Also, a drug can be used in a form that, uponrelease from the device, is converted by enzymes, hydrolyzed by body pHor other metabolic processes to the original form, or to a biologicallyactive form.

Specific examples of drugs that may be adapted for use include,Angiotensin-converting enzyme (ACE) inhibitors such as enalapril,lisinapril, and captopril; barbiturates such as pentobarbital sodium,phenobarbital, secobarbital, thiopental and mixtures thereof;heterocyclic hypnotics such as dioxopiperidines and glutarimides;hypnotics and sedatives such as amides and ureas, exemplified bydiethylisovaleramide and α-bromo-isovaleryl urea; hypnotic and sedativeurethanes and disulfanes; psychic energizers such as isocarboxazid,nialamide, imipramine, amitryptyline hydrochloride, pargylene, andprotryptyline hydrochloride; tranquilizers such as chloropromazine,promazine, fluphenzaine, reserpine, deserpidine, and meprobamate;benzodiazepines such as diazepam and chlordiazepoxide; anticonvulsantssuch as primidone, phenytoin, and ethosuximide; muscle relaxants andantiparkinson agents such as mephenesin, methocarbomal, cyclobenzaprinehydrochloride, trihexylphenidyl hydrochloride, levodopa/carbidopa, andbiperiden; antihypertensives such as α-methyldopa and thepivaloyloxyethyl ester of α-methyldopa; calcium channel blockers such asnifedipine, felodipine, diltiazem hydrochloride, diltiazem malate andverapamil hydrochloride; analgesics such as morphine sulfate, codeinesulfate, meperidine, and nalorphine; antipyretics and antiinflammatoryagents such as aspirin, indomethacin, ibuprofen, sodium indomethacintrihydrate, salicylamide, naproxen, colchicine, fenoprofen, sulindac,diflunisal, diclofenac, indoprofen and sodium salicylamide; localanesthetics such as procaine, lidocaine, tetracaine and dibucaine;antispasmodics and muscle contractants such as atropine, scopolamine,methscopolamine, oxyphenonium, papaverine; prostaglandins such as PGE₁,PGE₂, PGF_(2a) ; antimicrobials and antiparasitic agents such aspenicillin, tetracycline, oxytetracycline, chlorotetracycline,chloramphenicol, thiabendazole, ivermectin, and sulfonamides;antimalarials such as 4-aminoquinolines, 8-aminoquinolines andpyrimethamine; hormonal and steroidal agents such as dexamethasone,prednisolone, cortisone, cortisol and triamcinolone; androgenic steroidssuch as methyltestosterone; estrogenic steroids such as 17α-estradiol,α-estradiol, estriol, α-estradiol 3-benzoate, and 17-ethynylestradiol-3-methyl ether; progestational steroids such as progesterone;sympathomimetic drugs such as epinephrine, phenylpropanolaminehydrochloride, amphetamine, ephedrine and norepinephrine; hypotensivedrugs such as hydralazine; cardiovascular drugs such as procainamidehydrochloride, amyl nitrite, nitroglycerin. dipyridamole, sodium nitrateand mannitol nitrate; diuretics such as chlorothiazide, acetazolamide,methazolamide, hydrochlorothiazide, amiloride hydrochloride andflumethiazide, sodium ethacrynate, and furosemide; antiparasitics suchas bephenium, hydroxynaphthoate, dichlorophen and dapsone;antineoplastics such as mechlorethamine, uracil mustard, 5-fluorouracil,6-thioguanine and procarbazine; β-blockers such as pindolol,propranolol, metoprolol, oxprenolol, timolol maleate, atenolol;hypoglycemic drugs such as insulin, isophane insulin; protamine zincinsulin suspension, globin zinc insulin, extended insulin zincsuspension, tolbutamide, acetohexamide, tolazamide and chlorpropamide;antiulcer drugs such as cimetidine, ranitidine, famotidine andomeprazole; nutritional agents such as ascorbic acid, niacin,nicotinamide, folic acid, choline, biotin, pantothenic acid; essentialamino acids; essential fats; ophthalmic drugs such as timolol maleate,pilocarpine nitrate, pilocarpine hydrochloride, atropine sulfate,scopolamine; electrolytes such as calcium gluconate, calcium lactate,potassium chloride, potassium sulfate, sodium fluoride, ferrous lactate,ferrous gluconate, ferrous sulfate, ferrous fumurate and sodium lactate;and drugs that act on α-adrenergic receptors such as clonidinehydrochloride; analgesic drugs such as acetaminophen, oxycodone,hydrocodone, and propoxyphene; antihypercholesterolemic drugs such assimvastatin, pravastatin, lovastatin and genfibrozil; antiinfectivedrugs such as cefoxitin, cefazolin, cefotaxime, ciprofloxacin,cephalexin, norfloxacin, amprolium, ampicillin, amoxicillin, cefaclor,erythromycin, nitrofurantoin, minocycline, doxycycline, cefadroxil,miconazole, clotrimazole, phenazopyridine, clorsulon, fludalanine,pentizidone, cilastin, phosphonomycin, imipenem; gastrointestinal drugssuch as bethanechol, clidinium, dicyclomine, meclizine,prochlorperizine, trimethobenzamide, loperamide, diphenoxylate, andmetoclopramide; anticoagulant drugs such as warfarin, phenindione, andanisindione; 5α-reductase inhibitors such as Proscar and other drugssuch as trientine, cambendazole, ronidazole, rafoxinide, dactinomycin,asparaginase, nalorphine, rifamycin, carbamezepine, metaraminolbitartrate, allopurinol, probenecid, diethylpropion, dihydrogenatedergot alkaloids, nystatin, pentazocine, phenylpropanolamine,phenylephrine, pseudoephedrine, trimethoprim, and ivermectin.

The above list of drugs is not meant to be exhaustive. Many other drugswill certainly work in the instant invention.

By "therapeutically effective amount" is meant that the quantity ofbeneficial agent contained in the core, which can be delivered to theenvironment of use, has been demonstrated to be sufficient to induce thedesired effect during studies utilizing the beneficial agent.

Other excipients such as lactose, magnesium stearate, microcrystallinecellulose, starch, stearic acid, calcium phosphate, glycerolmonostearate, sucrose; polyvinylpyrrolidone, gelatin, methylcellulose,sodium carboxymethylcellulose, sorbitol, mannitol, polyethylene glycoland other ingredients commonly utilized as stabilizing agents or to aidin the production of tablets may also be present in the core.

The drug can be in the core as a dispersion, particle, granule, orpowder. Also, the drug can be mixed with a binder, dispersant,emulsifier or wetting agent and dyes.

The active agent may comprise from 0.01% to 75% of the core weight.Generally, the device can house from 0.05 ng to 50 grams of active agentor more, with individual devices containing, for example, 25 ng, about 1mg, about 5 mg, about 250 mg, about 500 mg, about 1.5 g, or the like.

The "polymer which upon hydration forms gelatinous microscopicparticles" useful in the novel device of this invention broadlyencompasses any polymer that, upon hydration, is capable of producingdiscrete gelatinous microscopic particles which support a dispersion,including the beneficial agent, as it forms. The gel forming polymerused also must exude from the core surface in such a way that thebeneficial agent is carried into the environment of use. Upon hydration,the gelatinous microscopic particles must be predisposed to leave thesurface taking the drug with it. This assures a constant surface areaexposed to the solvent of the environment of use and maintains theappropriate rate of release.

Polymers that form usable gelatinous microscopic particles, include thesuperabsorbant polymers such as "AQUAKEEP J550", "AQUAKEEP J400","CARBOPOL 974P" and "CARBOPOL 934P" and their pharmaceuticallyacceptable salts. By "pharmaceutically acceptable salts" of the polymersis meant the acid form of the polymer neutralized by converting all or aportion of the free acid functional groups to their salt form. The coreof the device contains from 5% to 75% by weight of the dry microscopicparticle polymer.

The "polymer hydration modulator" useful in the novel device of thisinvention broadly encompasses any water soluble compound that caninhibit or enhance the rate of hydration of the gel forming polymer ofthe core. Among the groups of compounds that can exert this effect areacids, bases, and the salts of acids and bases such as adipic acid,citric acid, fumaric acid, tartaric acid, succinic acid, sodiumcarbonate, sodium bicarbonate, betaine hydrochloride, sodium citrate,arginine, meglamine, sodium acetate, sodium phosphates, potassiumphosphates, calcium phosphate, ammonium phosphate, magnesium oxide,magnesium hydroxide, sodium tartrate and tromethamine. Other compoundsthat can be used as polymer hydration modifiers include sugars such aslactose, sucrose, mannitol, sorbitol, pentaerythritol, glucose anddextrose. Polymers such as microcrystalline cellulose and polyethyleneglycol as well as surfactants and other organic and inorganic salt canalso be used to modulate polymer hydration.

The hydration modulating agents are solubilized by the aqueous media ofthe environment and establish an environment such that the pH, ionicstrength or hydrophilic character is appropriate for the desired polymermicroscopic gel bead hydration rate. For example, these hydrationmodulating agents can enhance or retard the neutralization of acidicfunctional groups on the polymer which affects the rate of hydration.

The core compartment containing the drug, hydration modulator, andmicroscopic particle polymer as described herein, is typically in theform of a solid conventional tablet. Generally, the core is compressedinto its final shape using a standard tablet compressing machine. Thecore may contain compressing aids and diluents such as lactose thatassist in the production of compressed tablets. The core can becomprised of a mixture of agents combined to give the desiredmanufacturing and delivery characteristics. The number of agents thatmay be combined to make the core is substantially without an upper limitwith the lower limit equaling two components: the gel forming polymerand the beneficial agent.

The preferred specifications for the core are summarized below andinclude:

1. Core Drug Loading (size): about 0.01% to about 75% by weight of thetotal core mass or about 0.05 nanogram to about 50 grams or more(includes dosage forms for humans and animals).

2. Polymer Hydration. Modulator: 0% to about 75% by weight of the totalcore mass.

3. Gel Forming Polymer: about 5 to about 75% by weight of the total coremass.

In cases where the drug, the gel forming polymer and polymer hydrationmodulating agent exhibit the desired release rate, stability, andmanufacturing characteristics, there is no critical upper or lower limitas to the amount of drug that can be incorporated into a core mass. Theratio of drug to excipient is dictated by the desired time span andprofile of release, and the pharmacological activity of the drug.

Generally the core will contain 1% to 50% by weight of an beneficialagent admixed with other solute(s). Representative of compositions ofmatter that can be released from the device and can function as a soluteare, without limitation, those compositions as described.

The coating, applied to the core of the invention, is a material that isimpermeable and insoluble in the fluid of the environment of use, canform films, and does not adversely affect the drug, animal body, orhost. The coating is impermeable to water and also impermeable to theselected product, drugs, polymer hydration modulating agents, or toother compounds in the device. This impermeable material is insoluble inbody fluids and non-erodible or it can be bioerodible after apredetermined period with bioerosion following the end of the activedrug release period. In each instance, it is impermeable to solvent andsolute(s) and is suitable for construction of the device.

By "impermeable" is meant that the influx of water across the coating isde minimus. Flux of water into the device is via the apertures placed inthe coating.

The polymeric coating is applied to and adheres to the entire surface ofthe core. Apertures are produced in the coating to expose the core,using either a drill, a coring device or any other pharmaceuticallyaccepted means.

The apertures allow liquids from the environment of use to make contactonly with exposed portions of the core when in use. The number, size andconfiguration of the apertures is chosen to provide the release raterequired to suit a pharmacologically recognized requirement since thegel dispersion can form only where the apertures allow such core-liquidcontact.

The coating can be applied by dipping the cores into a suitable solutionof the polymer or by coating the cores with a pharma-acceptable polymercoating process. Among the groups of polymers that can provide this typeof protection are cellulose acetate, cellulose acetate butyrate,ethylcellulose, polyvinylacetate, polyvinyl chloride and polymers ofacrylic and methacrylic acid esters. In addition, other materials may beincluded with the coating to enhance its stability, color, elasticity,ease of application or opacity. These include plasticizers such asdibutylsebacate, diethylphthalate, triethylcitrate and polyethyleneglycol.

The coating is applied to a thickness of from 1 to 1000 microns butpreferably 10 to 500 microns typically, although thinner and thickercoatings fall within the scope of the invention.

The expression "aperture" as used herein, refers to ports through thecoating which expose the surface of the core to the environment. Thesize and number of apertures is chosen to effect the desired releaserate. Exposure of from about 1% to about 75% of the core surface iscontemplated by this invention.

The apertures are generally positioned in a regular pattern on bothfaces of the device although they can be positioned anywhere on the coreincluding the edges or all on one face.

The apertures are generally circular but may be of any design thatresults in the proper release rate. When the aperture is circular, itsdiameter ranges from about 0.1 mm to about 20 mm with diameters of about0.2 to 3.5 mm typical. The number of apertures in each device may rangefrom about 2 to about 1000 or more. Typically, the number of aperturesin each dosage form ranges from about 5 to about 100.

The apertures may be made by drilling the appropriate size hole throughthe coating using a mechanical or laser-based process. In the preferredembodiment, a digital laser marking system is used to drill the holesrequired. This system allows for an array of apertures to be drilled onboth faces of a dosage form simultaneously and at rates suitable forproduction of dosage forms.

The process utilizes a digital laser marking system (for example theDigiMark® variable marking system, available from Directed Energy, Inc.)to produce an unlimited number of holes through the surface or coatingof the dosage form, at rates practically suitable for production ofdosage forms.

The steps involved in this laser drilling process are as follows: adigital laser marking system is focused at a laser stage; the dosageform is moved onto the laser stage of the digital laser marking systemis pulsed to energize those laser tubes needed to drill the desiredapertures along a linear array on the dosage form, the dosage form ismoved forward on the laser stage and the digital laser marking system isagain pulsed as needed to produce an additional linear array ofapertures; the dosage form is then removed from the laser stage.

Additional, preferred specifications for the impermeable wall include: amixture of eight parts by weight of cellulose acetate butyrate, twoparts by weight of cellulose acetate and one part by weight ofdiethylphthalate. This mixture is dissolved in a solution of methylenechloride and methanol (about 3:1 v/v) and sprayed onto the cores to athickness of about 250 microns. Another preferred coating consists offive parts by weight of cellulose acetate butyrate and one part byweight of triethyl citrate dissolved in a mixture of acetone andmethanol (about 3:1 v/v). This mixture is sprayed on the core or dippedinto the mixture so that a coating of 100 microns is applied.

The polymers used in the coating which are herein described are known tothe art or can be prepared according to the procedures in Encyclopediaof Polymer Science and Technology, Vol. 3, published by IntersciencePublishers, Inc., New York, in Handbook of Common Polymers by Scott, J.R. and Roff, W. J., 1971, published by CRC Press, Cleveland, Ohio.

The following examples illustrate the preparation of the drug deliverydevice of this invention and their controlled release of one or moretherapeutically active ingredients into an environment of use and assuch are not to be considered as limiting the invention set forth in theclaims appended hereto.

EXAMPLES

In the following examples, the hydroxymethylglutaryl-coenzyme Areductase inhibitors (HMG CoA reductase inhibitors) simvastatin andlovastatin are used as model drugs. These drugs are highly effective inthe reduction of serum cholesterol levels in humans and possess neitheracidic nor basic functionality. The aqueous solubilities of simvastatinand lovastatin are 0.03 mg/ml and 0.00044 mg/ml respectively, at 20° C.The generation of a dispersion, in situ, from the components of a solidcore is disclosed. The anti-arthritic, indomethacin and the analgesic,acetaminophen serve as examples of beneficial agents which aredeliverable with this device. This permits the successful formulation ofpoorly aqueous soluble (simvastatin, lovastatin, indomethacin),moderately soluble (acetominophren) and freely water soluble drugs intoa delivery device.

Example 1

Tablets for the controlled release of the drug indomethacin were made asfollows, utilizing a 1:1 weight ratio of drug: J-550 polymer.

    ______________________________________    Core Component      Weight (g)    ______________________________________    "AQUAKEEP J-550"    2    Indomethacin        2    Avicel PH 101       400 mg    Povidone (K29-32)   60 mg in 6 ml EtOH    ______________________________________

Indomethacin, J-550 and Avicel were mixed thoroughly and granulated withthe polyvinylpyrrolidone as a 1% by weight solution in ethyl alcohol.The solvated mass was passed through a sieve of standard mesh size 18then dried overnight at 45° C. Tablet cores were prepared from theresulting granulation by taking approximately 115 mg of the granules andcompressing them on a Carver® press using 1/4" standard concave punches.

The tablet cores prepared as above were coated with polyvinyl chloride(PVC) coating by dip coating 5 times in diluted clear polyvinyl chloridecement. These tablets were rolled on edge each time on a teflon sheet toprevent sticking. Each tablet was allowed to dry approximately one hourbetween subsequent coatings and the tablets were dried for approximately8 hours after the fifth coat was applied. Five 1.5 mm diameter circularopenings were drilled through the coating on each face of the tablets.

The release of indomethacin from the coated, drilled tablets into 900 mlof pH 7.5 phosphate buffer at 37° C. with 100 rpm stirring was thendetermined (USP Apparatus 2). The absorbance of indomethacin wasmeasured at 320 nm using a Cary-14 spectrophotometer. Indomethacinrelease profiles for the coated, drilled dosage forms are shown in FIG.2.

Example 2

Tablets were prepared according to the procedure of Example 1, exceptthat the core mixture comprised indomethacin and J-550 polymer in theweight ratio of 1:3. Indomethacin release rates were determined as inExample 1 and are shown in FIG. 2.

Examples 3 and 4

Tablets were prepared according to the procedures of Examples 1 and 2.Core compositions of indomethacin and J-550 in a weight ratio of 1:1 and1:3 were spray coated with cellulose acetate butyrate CAB 381-20(Eastman Fine Chemicals) in a Freund® Model HCT-Mini Hi-Coater (8-inchpan) from a methylene chloride:methanol (1:1) solution at 4% by weightsolids. Coating thicknesses were 250 microns for the 1:1indomethacin:J-550 core composition and 400 microns for the 1:3 corecomposition. The indomethacin release rates were determined as inExample 1 and are shown in FIG. 2.

Example 5

Tablets for the controlled release of simvastatin were prepared from thefollowing formulation:

    ______________________________________    Ingredient       mg/Tablet    ______________________________________    Simvastatin      100    "AQUAKEEP J-550" 100    Avicel PH101     100    Povidone (K29-32)                     7.8    Magnesium Stearate                     1.5    Total            309.3    ______________________________________

The dry ingredients with the exception of magnesium stearate werethoroughly mixed and granulated with absolute alcohol. The solvated masswas passed through a No. 18 stainless steel sieve and then dried fortwenty-four hours at 37° C. The dried granules were forced through a No.35 mesh stainless steel sieve before lubricating with magnesiumstearate. This homogeneous mixture was compressed into tablets using 3/8inch standard concave round punches. The tablets were compressed to ahardness of 19 kg. The tablets were coated in a Freund® Model HCT-MiniHi-Coater (8-inch pan) to a thickness of 250 microns using the followingcoating formulation:

    ______________________________________    Ingredient              Amount    ______________________________________    Cellulose Acetate Butyrate CAB                            48     g    381-20    Cellulose Acetate CA 435-75S                            12     g    Methylene Chloride      2250   ml    Methanol                750    ml    Diethylphthalate        6      g    ______________________________________

Circular openings in the coating were made using a tubular boring toolwith an i.d. of 2.80 mm which provided openings of nearly 3.0 mm. The invitro release of simvastatin from tablets with three circular openingsof 3.0 mm diameter on each face was carried out at 37° C. using USPApparatus 2 into pH 7.4 phosphate buffer with 0.5% by weight weightsodium dodecyl sulfate at 100 rpm. The results are shown in FIG. 3.

Example 6

Tablets for the controlled release of lovastatin were prepared from thefollowing formulation:

    ______________________________________    Ingredient         mg/Tablet    ______________________________________    Lovastatin         20    "CARBOPOL 974P"    13.4    Sodium Citrate Dihydrate                       13.3    Lactose Hydrous (spray dried)                       13.3    Povidone (K29-32)  3.0    Total              63.0    ______________________________________

The ingredients were combined and thoroughly mixed in a mortar andpestle, then granulated with 90% alcohol: 10% by volume water. This wetmass was passed through a No. 20 stainless steel sieve and driedovernight at 40° C. The resulting mixture was compressed into tabletsusing 1/4 inch standard concave punches. The tablets were compressed toa thickness of 2.33 mm and a hardness of 9 kg.

The tablets were coated to a thickness of 250 microns with the followingformulation using a Freund® Model HCT-Mini H-Coater (8-inch pan).

    ______________________________________    Ingredient               Amount    ______________________________________    Cellulose Acetate Butyrate CAB 381-20                             64     g    Cellulose Acetate CA 435-755                             16     g    Methylene Chloride       3000   ml    Methanol                 1000   ml    Diethylphthalate         8      g    ______________________________________

In vitro release tests were carried out at 37° C. using USP Apparatus 2into pH 7.4 phosphate buffer containing 0.2% sodium dodecyl sulfate at50 rpm. The drug released was monitored by flow-through UVspectrophotometry. The drug released from coated tablets with 1.75 mmdiameter circular openings bored through the coating on each face isshown in FIG. 4.

Example 7

Simvastatin tablets were prepared from the following formulation:

    ______________________________________    Ingredients            mg/Tablet    ______________________________________    Simvastatin            40    CARBOPOL ® 974P    26.7    Sodium Citrate Dihydrate (milled to 100-200                           26.7    mesh)    Lactose Hydrous NF (spray dried)                           26.6    Povidone USP (K29-32)  6.0    Butylated Hydroxyanisole NF                           0.04    Magnesium Stearate NF  0.6    Total                  126.64    ______________________________________

The simvastatin, CARBOPOL®, milled sodium citrate, lactose andpolyvinyl-pyrrolidone were combined, mixed thoroughly and granulatedwith 10% by weight water in alcohol containing the required BHA. The wetmass was forced through a No. 18 sieve and dried overnight. The drygranulation was lubricated with magnesium stearate and the homogenousmixture compressed using 1/4 inch standard concave round tooling and acompression force of 1000 lbs. The compressed tablets had a thickness of3.89 mm and a hardness of 10 kg. The tablets were spray coated to a coatthickness of 100 microns in a Freund® HCT-Mini Hi-Coater (8-inch pan)using the following coating formulation:

    ______________________________________    Ingredient               Amount    ______________________________________    Cellulose Acetate Butyrate CAB 381-20                             80     g    Triethyl Citrate         16     g    Acetone                  3000   ml    Methanol                 1000   ml    ______________________________________

In vitro release tests were carried out at 37° C. using USP Apparatus 2into pH 7.4 phosphate buffer containing 0.4% by weight sodium dodecylsulfate at 50 rpm. The drug released was monitored by flow-through UVspectrophotometry. The results for tablets with one 2.8 mm diametercircular opening per tablet face are shown in FIG. 5.

Example 8

Tablets for the controlled release of lovastatin were prepared from thefollowing formulation:

    ______________________________________    Ingredient           mg/Tablet    ______________________________________    Lovastatin           40    CARBOPOL 974P NF     16    Sodium Citrate USP (dihydrate)                         32    Lactose Hydrous NF (spray dried)                         16    Povidone USP (K29-32)                         5.2    Butylated Hydroxyanisole NF                         0.04    Magnesium Stearate NF                         0.55    Total                109.79    ______________________________________

The granular sodium citrate dihydrate was reduced in particle size suchthat 90% by weight went through a No. 120 mesh sieve. The milled sodiumcitrate dihydrate was combined with lovastatin, CARBOPOL®, lactose andpolyvinylpyrrolidone, mixed thoroughly then granulated using AlcoholUSP. The solvated mass was passed through a #10 screen then driedovernight at 50° C. The dried granulation was milled, then lubricatedwith magnesium stearate. The homogeneous mixture was compressed intotablets using 1/4 inch standard concave tooling. The tablets werecompressed to a thickness of 3.43 mm and a hardness of 10.5 kg. Thetablets were coated to a thickness of 100 microns with the followingcoating formulation using a Glatt WSG-3 fluidized bed column spraycoater.

    ______________________________________    Ingredients              Amount    ______________________________________    Cellulose Acetate Butyrate (CAB 381-20)                             80     g    Triethyl Citrate NF      16     g    Acetone NF               3000   ml    Alcohol USP              1000   ml    ______________________________________

In vitro release tests were carried out as in Example 7 for tablets withbored circular openings of 1.5 mm diameter and three per tablet face.The results are shown in FIG. 6.

Example 9

Tablets for the controlled release of acetaminophen were preparedaccording to the following formulation:

    ______________________________________    Ingredient         mg/Tablet    ______________________________________    Acetaminophen      20    CARBOPOL ® 974P                       10    Sodium Citrate Dihydrate                       20    Lactose Hydrous (spray dried)                       10    Povidone (K29-32)  3    Total              63    ______________________________________

The ingredients above were combined, mixed thoroughly then granulatedwith alcohol. The solvated mass was passed through a No. 20 mesh sieveand dried overnight at 40° C. The dried granulation was compressed intotablets using 1/4 inch standard concave tooling. The tablets werecompressed to a thickness of 2.31 mm and a hardness of 6-7 kg. Thetablets were coated as in Example 6.

In vitro release tests were carried out at 37° C. using USP Apparatus 2into pH 7.4 phosphate buffer at 50 rpm. The drug released was monitoredby flow-through UV spectrophotometry. The results for tablets with one2.75 mm diameter circular opening per tablet are shown in FIG. 7.

Example 10

Tablets cores containing lovastatin, CARBOPOL® 974P, trisodium citrateand lactose in relations of 5:2:4:2 were prepared using the proceduredescribed in Example 8.

Varying numbers of apertures were mechanically drilled in each face ofthe coated tablets. The diameter of the apertures ranged from about 0.23mm to about 3 mm in diameter as measured by microscopic imaging using anAnalytical Imaging Concepts IM4000. In vitro release tests wre carriedout at 37° C. using USP Apparatus 2 in pH 7.4 phosphate buffercontaining 0.4% sodium dodecyl sulfate at 50 rpm. The drug released wasmonitored by flow-through UV spectrophotometry.

The results of the study are shown in Table I.

Example 11

Twenty-four (24) apertures of 0.35 mm in diameter were drilled in eachface of the coated tablets prepared for the study in Example 10 usingthe DIGIMARK™ digital laser marking system. The apertures were measuredby microscopic imaging using an Analytical Imaging Concepts IM4000.Release rates were studied as in Example 10. The results are shown inTable II.

                  TABLE I    ______________________________________                                         Release           Initial Drug                       Hole              Rate/Hole    Number of           Release Rate                       Diameter Hole Surface                                         Surface Area    holes  (mg/h) (mg/h)                       (m/m)    Area (m/m.sup.2)                                         (mm/h)/mm.sup.2    ______________________________________    5      0.4         0.23     0.42     1.06    10     0.91        0.23     0.83     1.10    20     2.14        0.23     1.66     1.29    40     3.57        0.23     3.32     1.07    1      0.35        0.53     0.44     0.79    3      1.03        0.53     1.32     0.78    5      1.92        0.53     2.21     0.87    10     3.36        0.53     4.41     0.76    5      4.28        1.07     8.99     0.48    7      5.80        1.07     12.59    0.46    1      1.96        1.6      4.02     0.49    2      3.55        1.6      8.04     0.44    3      5.07        1.6      12.06    0.42    1      2.22        2.0      6.28     0.35    1      2.73        2.4      9.05     0.30    1      4.17        3.0      14.14    0.29    ______________________________________

                  TABLE II    ______________________________________                                    Release             Initial Drug           Rate/Hole    Number of             Release Rate Hole Surface                                    Surface Area    holes    (mg/h)       Area (m/m.sup.2)                                    (mg/h)/mm.sup.2    ______________________________________    24       3.96         4.62      0.86    ______________________________________

Example 12

Tablets for the controlled release of nifedipine were prepared from thefollowing formulation:

    ______________________________________    Ingredient           mg/Tablet    ______________________________________    Nifedipine micronized                         69    CARBOPOL 974P NF     30    Dibasic Sodium Phosphate                         75    (anhydrous) USP    Lactose Hydrous NF (spray dried)                         15    Povidone USP K-90    5    Magnesium Stearate NF                         0.88    Total                194.88    ______________________________________

The nifedipine was milled using the Model 00 Jet-O-Mizer to a 10 micronmedian particle size. The micronized nifedipine was combined withdibasic sodium phosphate, carbopol, lactose and polyvinylpyrrolidone,mixed thoroughly then granulated using an aqueous alcoholic solventblend (10% by volume water). The solvated mass was passed through a #20screen then dried initially at 60° C. for two to four hours, then at 40°C. overnight. Magnesium stearate was sifted over the dried granulationand the total mixture passed through a #40 screen. The homogenousmixture was compressed into tablets using 5/16 inch standard concavetooling. The tablets were compressed to a thickness of 3.6 mm and ahardness of 20 kg. The tablets were coated to a thickness of 100 micronswith the following coating formulation using a UniGlatt fluidized bedcolumn spray coater.

    ______________________________________    Ingredient                Amount    ______________________________________    Cellulose Acetate Butyrate (Eastman 381-20)                              140    g    Triethyl Citrate NF       14     g    Methylene Chloride        3000   ml    Alcohol USP               1000   ml    ______________________________________

The tablets were mechanically drilled with 18-0.45 mm diameter openingthrough the coating on each face then overcoated to a thickness ofapproximately 150 microns with the following coating formulation using aUniGlatt fluidized bed column spray coater.

    ______________________________________    Ingredient                Amount    ______________________________________    Hydroxypropyl Methylcellulose (Methocel E5)                              100    g    Ethylcellulose (Ethocel E10)                              25     g    Water                     100    ml    Alcohol                   1000   ml    Methylene Chloride        2500   ml    ______________________________________

In vitro release tests were carried out at 37° C. using USP Apparatus 2into pH 7.4 phosphate buffer containing 2% sodium dodecyl sulfate at 100rpm. The drug released was monitored by flow-through UVspectrophotometry at 340 nm.

What is claimed is:
 1. A drug delivery device for the controlled in situproduction and release of a dispersion containing simvastatin, whichis:(A) a compressed core prepared from an admixture comprising:(i) atherapeutically effective amount of simvastatin; and (ii) a polymerwhich upon hydration forms gelatinous microscopic particles, wherein thepolymer is selected from the group consisting of sodium polyacrylate,carboxypolymethylenes, and the pharmaceutically acceptable saltsthereof, and wherein the carboxypolymethylenes are prepared from acrylicacid crosslinked with allylethers of sucrose or pentaerythritol; and (B)a water insoluble, water impermeable polymeric coating comprising apolymer and a plasticizer, which surrounds and adheres to the core,wherein the polymer is selected from the group consisting of celluloseacetate, cellulose acetate butyrate, ethylcellulose, polyvinylacetate,polyvinyl chloride, polymers of acrylic and methacrylic acid esters, andcombinations of these polymers, and the plasticizer is selected from thegroup consisting of dibutylsebacate, diethylphthalate, triethylcitrateand polyethylene glycol, the coating having a plurality of formedapertures exposing between about 1 and about 75% of the core surface;andwherein the release rate of the beneficial agent from the device is afunction of the number and size of the apertures.
 2. The device of claim1 wherein the amount of simvastatin in the core comprises from 0.01% to75% by weight of the core mixture.
 3. The device of claim 1 wherein theamount of polymer which upon hydration produces gelatinous microscopicparticles in dry form comprises from about 5% to about 75% by weight ofthe core mixture.
 4. The device of claim 1 wherein the water insoluble,water impermeable polymeric coating is comprised of a polymer selectedfrom the group consisting of polyvinyl chloride, cellulose acetate,cellulose acetate butyrate, ethylcellulose and combinations of thesepolymers; and a plasticizer selected from the group consisting ofdiethylphthalate, dibutylsebacate and triethylcitrate.
 5. The device ofclaim 1 wherein the polymer in the water insoluble, water impermeablepolymeric coating is cellulose acetate butyrate.
 6. The device of claim1 wherein the plasticizer in the water insoluble, water impermeablepolymeric coating is triethylcitrate.
 7. The device of claim 1 whereinthe polymer which upon hydration forms gelatinous microscopic particlesis selected from the group consisting of carboxypolymethylenes preparedfrom acrylic acid crosslinked with allylethers of sucrose orpentaerythritol, and the pharmaceutically acceptable salts thereof. 8.The device of claim 1 wherein the compressed core further comprises atleast one polymer hydration modulating agent selected from the groupconsisting of acids, bases, salts, sugars, surfactants, and solublepolymers.
 9. The device of claim 8 wherein the polymer hydrationmodulating agent or agents are selected from the group consisting ofsodium phosphates and microcrystalline cellulose.
 10. The device ofclaim 1 wherein the compressed core is further comprised of one or morecompressing aids and diluents.
 11. The device of claim 1 wherein thecompressed core is further comprised of lactose.
 12. The device of claim1 wherein the apertures in the coating range from 0.1 mm to 20 mm attheir widest point.
 13. The device of claim 1 wherein the number ofapertures ranges from 2 to
 1000. 14. The device of claim 13 wherein thenumber of apertures ranges from 5 to
 100. 15. The device of claim 1wherein the apertures are positioned in a regular pattern on both facesof the device.
 16. The device of claim 1 further comprised of at leastone material for enhancing at least one of the characteristics of thewater impermeable polymeric coating, wherein the characteristics areselected from the group consisting of stability, color, elasticity, easeof application, and opacity.
 17. The device of claim 16 comprised of atleast one material for enhancing the elasticity of the water impermeablepolymeric coating.
 18. The device of claim 16 comprised of at least onematerial for enhancing the opacity of the water impermeable polymericcoating.
 19. The device of claim 16 comprised of at least one materialfor enhancing the ease of application of the water impermeable polymericcoating.
 20. A drug delivery device for the controlled in situproduction and release of a dispersion containing simvastatin, whichis:(A) a compressed core prepared from an admixture comprising:(i) from0.01% to 75% by weight of the core mixture of a therapeuticallyeffective amount of simvastatin; and (ii) from about 5% to about 75% byweight of the core mixture of a polymer which upon hydration formsgelatinous microscopic particles, wherein the polymer is selected fromthe group consisting of sodium polyacrylate, carboxypolymethylenes andthe pharmaceutically acceptable salts thereof, and wherein thecarboxypolymethylenes are prepared from acrylic acid crosslinked withallylethers of sucrose or pentaerythritol; and (B) a water insoluble,water impermeable polymeric coating comprising a polymer and aplasticizer, which surrounds and adheres to the core, wherein thepolymer is selected from the group consisting of polyvinyl chloride,cellulose acetate, cellulose acetate butyrate, ethylcellulose andcombinations of these polymers, and the plasticizer is selected from thegroup consisting of diethylphthalate, dibutylsebacate andtriethylcitrate, the coating having a plurality of formed aperturesexposing between about 1 and about 75% of the core surface;and whereinthe release rate of drug from the device is a function of the number andsize of the apertures.
 21. The device of claim 20 wherein:the polymerwhich upon hydration forms gelatinous microscopic particles is selectedfrom the group consisting of carboxypolymethylenes prepared from acrylicacid crosslinked with allylethers of sucrose or pentaerythritol and thepharmaceutically acceptable salts thereof; the polymer in the waterinsoluble, water impermeable polymeric coating is cellulose acetatebutyrate; and the plasticizer in the water insoluble, water impermeablepolymeric coating is triethylcitrate.
 22. The device of claim 21 whereinthe compressed core is further comprised of at least one polymerhydration modulating agent selected from the group consisting of sodiumphosphates and microcrystalline cellulose.
 23. A process for thepreparation of a drug delivery device for the controlled in situproduction and release of a dispersion containing a beneficial agentcharacterized by having a compressed core surrounded by a waterinsoluble, water impermeable polymeric coating, comprising the stepsof:(A) preparing a uniform mixture by either dry mixing or wetgranulating a polymer which upon hydration produces gelatinousmicroscopic particles, the beneficial agent and other excipients used inthe preparation of the core, wherein the polymer is selected from thegroup consisting of sodium polyacrylate, carboxypolymethylenes, and thepharmaceutically acceptable salts thereof, and wherein thecarboxypolymethylenes are prepared from acrylic acid crosslinked withallylethers of sucrose or pentaerythritol; (B) compressing the uniformmixture into cores; (C) coating the entire core with the waterinsoluble, water impermeable polymeric coating comprised of a polymerand a plasticizer, wherein the polymer is selected from the groupconsisting of cellulose acetate, cellulose acetate butyrate,ethylcellulose, polyvinylacetate, polyvinyl chloride, polymers ofacrylic and methacrylic acid esters, and combinations of these polymers,and the plasticizer is selected from the group consisting ofdibutylsebacate, diethylphthalate, triethylcitrate and polyethyleneglycol; and (D) forming apertures through the coating.
 24. The processof claim 23 wherein the beneficial agent is simvastatin.
 25. The processof claim 23 wherein the uniform mixture of step (A) is prepared byeither dry mixing or wet granulating a polymer hydration modulatingagent with the polymer, the beneficial agent and the other excipients.26. The process of claim 25 wherein at least one material for enhancingat least one of the characteristics of the water impermeable coating isadded either before or after, or before and after, application of thewater impermeable polymeric coating, wherein the characteristics areselected from the group consisting of stability, color, elasticity, easeof application, and opacity.
 27. The process of claim 26 wherein thebeneficial agent is simvastatin.
 28. A drug delivery device for thecontrolled in situ production and release of a dispersion containingsimvastatin, which is:(A) a compressed core prepared from an admixturecomprising:(i) a therapeutically effective amount of simvastatin; and(ii) a polymer which upon hydration forms gelatinous microscopicparticles, wherein the polymer is selected from the group consisting ofsodium polyacrylate, carboxypolymethylenes, and the pharmaceuticallyacceptable salts thereof, and wherein the carboxypolymethylenes areprepared from acrylic acid crosslinked with allylethers of sucrose orpentaerythritol; and (B) a water insoluble polymeric coating comprisinga polymer and a plasticizer, which surrounds and adheres to the core,wherein the polymer is selected from the group consisting of polyvinylchloride, cellulose acetate, cellulose acetate butyrate, ethylcelluloseand combinations of these polymers, and the plasticizer is selected fromthe group consisting of diethylphthalate, dibutylsebacate, andtriethylcitrate, the coating having a plurality of formed aperturesexposing between about 1 and about 75% of the core surface; and whereinthe release rate of the beneficial agent from the device is a functionof the number and size of the apertures.